The effect of a certain substance can change through repetitive or
constant influx of a certain substance / medicine / drug. This process is called Adaptation.
If the effect of a certain dosage increases, by adaptation, it is called Sensitisation.
The overall decrease in effect after repeated consumption or constant influx of a
substance is called Tolerance (see Abb.19). The same dosage does not have the same
effect in life forms which have a certain tolerance; the dose must be increased in order
for the same effect to be reached. The development of tolerance can develop overall
differently and with varying chronological effects. The S-shape dosage-effect curve moves
to the right with higher dosages (decreased potency) or the maximum effect (Efficacy)
becomes less.

Fig.20: Pharmakodynamic Tolerance:
As the actual tolerance increases, the less the effect is of the next dose

The so-called tolerance, through habitation, occurs in two ways in the
body:

For the Tolerance of Morphine type (pharmacodynamic Tolerance, see Abb.20)
one sees a decrease in the number of receptors (down-regulation) and on the other
hand, an increase in the density of Adenylate Cyclases (up-regulation). When
chronic stimulation of the Opioid-receptors occurs, the cAMP-forming enzyme is permanently
inhibited. The organism reacts to this constant inactiveness by forming more
Enzyme-Proteins (Adaptation). The decrease in the presynaptic Opioid-receptors and the
thus increase in the Enzyme forces an increase in the formation of cAMP which leads to an
decrease of the inhibiting effect of the opioids on the neurotransmitter release. This
adaptation is for the opioids i.e. in the nozizeptive System, the most probable mechanism
in the development of tolerance: the small number of inhibiting, presynaptic contacts must
be compensated through an increase in activity resp. through a larger influx of opioids.
The endstation organ is decreasingly responsive. Tolerance from morphine type is observed
by all opioids which cause euphoria.

For the pharmacokinetic Tolerance, the body increases the amount of enzyme
for breaking down the substance in the liver and the Medicine / drug is then metabolised
faster and excreted. This enzyme induction plays a role in the breaking down of
barbiturates and many other medicines, such as Antiepileptika and Tuberkulostatika, but
also for Methadone. Enzyme induction mutually increases through the mentioned substance.
The substances are broken down faster through simultaneous medication. Pharmacokinetical
tolerance formation has to be compensated through an increase in dosage frequency. An
increase in dosage cannot be accommodated for due to large fluctuations in concentration
which occur through quick metabolism.

Tab.11: Different Tolerance against
Effects of Opioids

Pronounced

Middle

slight

Analgesic

Euphoria

Sedation

Dysphoria

Antidiuretic

Breathing Depression

Nausea (immediate
effect)

Antitussive effect

Bradykardia

Miosis

Constipation

Menstrual cycle
disruptions

Blocking effect of Antagonists

The opioid Methadone effects is decreased through two tolerance-forming
mechanisms: through the Enzyme induction forms the pharmacokinetical tolerance and the
pharmacodynamical through the reduction of the presynaptic opioid receptors. Enzyme
induction through barbiturates, Antiepileptica and  especially clinically and
quantitatively relevant  throughTuberculostatica (INH) is the metabolism of
methadone accelerated through Enzyme induction. Methadone is subject to an intensified
pharmacokinetic Tolerance forming mechanism during Tuberculosis treatment (see chapters 21
& 26.1).

Addicts usually consume opioids in doses which would be fatal for
people who are not used to it and are intolerant. Tolerance means that one can bear higher
doses and serum concentrations.

A habit is noticeable just after a few days of constant opioid
consumption. Sadly, there is no quantitative data about the chronological course of
tolerance development in people. (see Chapter 11)

Tolerance develops with the Opioid  receptors and is substance
specific (Koob 1992). The constant flux of opioids causes Cross tolerance against
the effects of the other Opioid agonists.

As the affinity of a substance to its receptor increases and as
the relative intrinsic activity becomes larger, so does the extent and speed
pharmacodynamic Tolerance formation increase. Opioid-tolerance develops visibly in
relation to pain inhibition, euphoria and central numbing; empirically, it seems that this
development takes a parallel course chronologically and quantitatively. The paralysis of
the respiratory centre under lies a slightly less obvious tolerance development. The
effects on the smooth muscle, the formation of disturbances in the cycles and the
formation of pin-pupils are observed in drug-dependent people, whether it is heroin,
morphine or methadone even when it is habitual, i.e. these effects show a substansibly
less tolerance development

Case 1: Opioid tolerance due to repetitive or chronic intake of
opioid doses is made up of many varied, single Adaptation processes in the different
neuronal and neurochemical systems. (Nestler 1994, 1996, Smart 1996, Kuhar 1996, Nutt
1996). The Expression of different proteins and peptides is changed and the number
of receptors is drastically decreased (down-regulation). Surprisingly, b-Endorphine concentrations in the brain
(compensating?) are raised through short term administering of the opioid agonists
Morphine, Heroin or Methadone and on the other hand, decreased through the antagonists,
Naloxon or during opioid abstinence (Kosten 1992). The b-Endorphin mirror in the brain normalises under constant effect of methadone
through chronic administering; on the other hand, the b-Endorphine concentrations, under chronic treatment with Naltrexon, stay
constantly high.

Opioids influence the ability to pay attention for simple and complex
stimuli / tasks (Gordon 1970, 1994). The level of endorphine is crucial (Rosenberg 1994).
Naltrexon decreases the area of attentivity for few key-stimuli (Arnsten 1981). Exogenic
opioid consumption disables the effect of endogenic peptides by competing for the opioid
receptors which are in a tolerant state. The large restriction in the range of feelings is
also, along with the restriction in attentivity, a possible consequence of Adaptation due
to opioid consumption: the euphoric highs as well as the feelings of uneasiness and
sensitivity are numbed.

On the basis of neurochemical results after abstinence from nicotine,
cocaine but also from opioids, are irreversible Adaptations mechanisms suspected (Dani
1996, Kuhar 1996, Smart 1996). The question of whether this is due to falling back into
the addiction is still open.